Key Laboratory of Smart Drug Delivery, Ministry of Education, & State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
ACS Nano. 2024 Jun 4;18(22):14348-14366. doi: 10.1021/acsnano.4c00480. Epub 2024 May 20.
Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.
周细胞功能障碍严重破坏脑血管完整性，并加剧阿尔茨海默病 (AD) 中的神经退行性变。然而，针对周细胞的治疗方法在 AD 领域仍未得到充分开发。受周细胞损伤中血管细胞黏附分子-1 (VCAM-1) 和活性氧 (ROS) 水平升高的启发，我们通过苯硼酸酯键将 VCAM-1 高亲和力肽 VHS 和神经保护载脂蛋白模拟肽 COG1410 的融合肽 VLC 与姜黄素 (Cur) 偶联，制备了一种多功能纳米药物 (VLC@Cur-NPs)，以减轻复杂的周细胞相关病理变化。重要的是，VLC@Cur-NPs 通过 VLC 有效归巢到周细胞损伤部位，并在 ROS 刺激下释放其内容物，以最大限度地发挥其调节作用。因此，VLC@Cur-NPs 显著增加了周细胞的再生，形成正反馈回路，从而改善了 APP/PS1 转基因小鼠的神经血管功能，并最终缓解了记忆缺陷。我们提出了一种有前景的 AD 治疗策略，该策略可以精确调节周细胞，并有潜力治疗其他脑血管疾病。
